Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Elife. 2024 Aug 27;13:RP96535. doi: 10.7554/eLife.96535.
Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking.
We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models.
Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, knockout mice.
Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.
South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes' legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123).
clinicaltrials.gov: NCT01803568.
身体活动与预防 2 型糖尿病和动脉粥样硬化性心血管疾病的发展有关。然而，我们对这些影响的确切分子机制的理解仍不完整，缺乏客观评估身体活动的良好生物标志物。
我们分析了 26 名男性的 3072 种血清蛋白，这些男性体重正常或超重，进行了 12 周的综合力量和耐力运动干预。我们使用高胰岛素正葡萄糖钳夹技术来估计胰岛素敏感性，测量最大耗氧量、肌肉力量，并使用 MRI/MRS 来评估身体成分和器官脂肪沉积。对肌肉和皮下脂肪组织活检进行 mRNA 测序。在英国生物银行的多达 47747 名个体的样本中以及使用两样本孟德尔随机化和小鼠模型进行了额外的关联分析。
经过 12 周的运动干预，我们观察到 283 种血清蛋白发生了显著变化。值得注意的是，这些蛋白质中有 66 种在超重男性中升高，并且在运动方案之前与肝脏脂肪呈正相关，但在运动后恢复正常。此外，对于 19.7%和 12.1%的运动反应蛋白，分别显示了肌肉和脂肪中相应的 mRNA 表达水平的变化。蛋白 CD300LG 在血液、肌肉和脂肪中均表现出一致的变化。血清 CD300LG 与胰岛素敏感性呈正相关，与肌肉和脂肪中的血管生成相关基因表达呈正相关。此外，血清 CD300LG 与英国生物银行中的体力活动呈正相关，与血糖水平呈负相关。在该样本中，血清 CD300LG 与体力活动之间的关联在男性中明显强于女性。孟德尔随机化分析表明，血清 CD300LG 水平与空腹血糖、口服葡萄糖耐量试验后 2 小时血糖和 HbA1c 之间存在潜在的因果关系。此外，在小鼠模型中，Cd300lg 对运动有反应，我们观察到雄性而非雌性 基因敲除小鼠糖耐量受损的迹象。
我们的研究鉴定了一些新的血清蛋白，其水平随长时间的运动而变化，与身体成分、肝脏脂肪和葡萄糖稳态有显著相关性。血清 CD300LG 随体力活动增加，与改善血糖水平有潜在因果关系。CD300LG 可能是一种有前途的运动生物标志物，也是 2 型糖尿病的治疗靶点。
南挪威地区健康管理局、西蒙·福格内斯基金、糖尿病协会、约翰·塞尔默·克瓦内斯的研究与防治糖尿病基金。英国生物银行资源参考号 53641。澳大利亚国家卫生和医学研究委员会研究员基金（APP2017942）。澳大利亚研究理事会发现早期职业奖（DE220101226）。挪威研究理事会项目资助（325640 号）和流动资助（287198 号）。奥斯陆大学医学研究生研究计划。诺和诺德基金会内分泌代谢学新兴卓越奖 2023 年（NNF23OC0082123）。
clinicaltrials.gov：NCT01803568。
